1. Field of the Invention
The present invention relates to liposomal dispersions containing un-neutralized salicylic acid and a process for their preparation. More particularly, the present invention relates to a cosmetic dispersion that allows for the incorporation of large amounts of salicylic acid within the hydrophobic compartment of the liposomal bilayer, without the necessity of pre-neutralization or salt formation of the corresponding salicylate, while simultaneously permitting the pH of the external aqueous compartment to be adjusted with soluble organic bases.
2. The Prior Art
Salicylic acid is an active ingredient long-known to those skilled in the formulation of cosmetic and topical products. Dandruff has been treated with ointments containing 2 percent salicylic acid. As a keratolytic agent, salicylic acid will soften and swell the epidermis. At concentrations higher than 2 percent, salicylic acid is an efficacious anti-acne agent and is bactericidal. The formation of salts of salicylic acid, such as sodium salicylate formed by the combination of salicylic acid and sodium hydroxide, greatly improves the water solubility of the free acid, but substantially modifies the biological response to salicylic acid.
Salicylic acid is nearly insoluble in water (limit of solubility approximately 0.2 percent at room temperature). When incorporated into cosmetic solutions, salicylic acid requires the addition of cosolvents such as ethanol, isopropanol or dimethylsulfoxide. These solutions exhibit low pH (approximately 2), and as a consequence may be irritating to the skin. Development of aesthetic cosmetic formulations under these constraints of pH greatly limits the range of formulation types. For example, hydrocolloid gels will not form at this extreme of pH. Many other cosmetic ingredients are rendered unstable under these conditions.
A general reference for the formulation of cosmetic compositions containing salicylic acid follows:
Wilkinson, J. B. and Moore, R. J. Harry's Cosmeticology (Seventh Edition), 1982, Chemical Publishing Co., Inc., New York, N.Y., pp. 19, 45, 122, 687, 366. PA1 Hayward, J. A. and Smith, W. P. Potential Applications of Liposomes in Cosmetic Science, in Cosmetic and Toiletries, 105: 47-54, 1990. PA1 a) an effective amount of polar lipids known to form, either alone or in combination, liposomal bilayers; PA1 b) an effective amount of salicylic acid; PA1 c) an effective amount of a polar, membrane-impermeant, water-soluble organic base; and, PA1 d) the balance up to 100 percent by weight of water based upon the total composition weight.
A general refernce for the application of liposomes to cosmetics follows:
The Won U.S. Pat. No. 5,145,675 is related to a topical delivery system for active ingredients such as salicylic acid, whereby controlled release is achieved by the gradual desorption of the active ingredient from solid, porous particles.
The Cioca et al U.S. Pat. No. 4,999,348 is related to cosmetic and pharmaceutical compositions containing liquid crystals and liposomes, and methods of incorporating such ingredients into cosmetic formulations.
The Desai et al U.S. Pat. No 4,816,247 is related to emulsions of ionizable hydrophobic drugs including hydroxybenzoic acid (salicylic acid).
The Popescu et al. U.S. Pat. 4,708,861 is related to liposome gel compositions.
The Allen U.S. Pat. No. 4,895,727 relates to topical treatment methods which utilize water-soluble zinc compound to enhance the reservoir effect of active ingredients in the skin, including salicylic acid.
The Story and Flynn U.S. Pat. No. 4,944,949 relates to micellar dispersions of non-steroidal anti-inflammatory drugs (NSAID's), such as salicylic acid, with surfactants such as polyethoxylated nonionics.
The Shroot et al. U.S. Pat. No. 5,151,534 relates to eicosenoid lipids and their application in pharmacy and cosmetics. These lipids may be formulated with salicylic acid and may be incorporated into liposomes.
The Tzeghai and Leis U.S. Pat. No. 4,755,387 relates to oral therapeutics, such as salicylic acid, which have a coating of lipids to provide release of the therapeutic in the intestines. The lipid coatings are non-liposomal, and are comprised of neutral lipids and esters.
The DuBois U.S. Pat. No. 5,075,113 relates to phospholipid-based emulsions of paraffins which may contain salicylic acid.
The Gajdos and Metzen U.S. Pat. No. 5,114,928 relates to solid dosage forms comprised of non-liposomal phospholipid and utilizes salicylic acid as a stabilizer.
The Dunphy et al. U.S. Pat. No. 5,085,856 relates to a formulation for a water-in-oil emulsion comprising phospholipids which may include liposomes, and, within the emulsion, salicylic acid.
The Weiner and Fielder U.S. Pat. No. 5,049,392 relates to a method of producing liposomes specifically via osmotic shock; the resultant liposomes may contain NSAID's including salicylic acid.
The Fountain U.S. Pat. No. 5,133,965 relates to a wound dressing comprised of liposomes generated by a solvent-dilution method; the resultant liposomes may contain salicylic acid.